PROJECT SUMMARY Cancer cells have been shown to be sensitive to apoptotic stimulus of tumor necrosis factor ?-related apoptosis-inducing ligand (TRAIL), whereas normal cells showed very little response. TRAIL was shown to be active as a single agent and exhibited synergistic activity with certain chemotherapeutic agents or radiotherapy, causing marked regression or complete remission of tumors. There is increasing evidence that membrane-bound TRAIL expressed on the surface of activated T-lymphocytes can enhance T-cell effector function and augment T-cell tumoricidal activity. The ability to genetically engineer primary T-cells creates new and highly promising prospects for tumor immunity and cancer treatment. The transduction of T-cells with genes encoding chimeric antigen receptors enables T-cell recognition of antigens that are either poorly immunogenic or ignored by the immune system. In addition, the ectopic expression of therapeutic ligands (e.g. TRAIL) can potently increase their tumoricidal activity. New strategies for tumor sensitization to TRAIL-based immunotherapies and modulation of TRAIL resistance are being developed and some can be translated to the clinic. Our central theme and hypothesis is that TRAIL overexpression by T-cells results in augmented apoptosis in tumor cells and that radiation and/or chemotherapy positively affect TRAIL-mediated tumor apoptosis during T-cell adoptive immunotherapy and can be used as a synergistic approach to enhance T-cell tumor targeting and effector function.